Salts of quinoline derivatives as nk3 antagonists

ABSTRACT

A compound of formula (I) or a solvate thereof, characterized in that salt comprises a compound of formula (I) in anionic form and a salting cation; a process for preparing such a compound, a pharmaceutical composition containing such a compound and the use of such a compound in medicine.

[0001] The present invention relates to novel compounds, in particularto salts of quinoline derivatives, to a process for the preparation ofsuch compounds, to pharmaceutical compositions containing such compoundsand to the use of such compounds and compositions in medicine.

[0002] The mammalian peptide Neurokinin B (NKB) belongs to theTachykinin (TK) peptide family which also include Substance P (SP) andNeurokinin A (NKA). Pharmacological and molecular biological evidencehas shown the existence of three subtypes of TK receptor (NK₁, NK₂ andNK₃) and NKB binds preferentially to the NK₃ receptor although it alsorecognises the other two receptors with lower affinity (Maggi et al,1993, J. Auton. Pharmacol., 13, 23-93).

[0003] Selective peptidic NK₃ receptor antagonists are known (Drapeau,1990 Regul. Pept., 31, 125-135), and findings with peptidic NK₃ receptoragonists suggest that NKB, by activating the NK₃ receptor, has a keyrole in the modulation of neural input in airways, skin, spinal cord andnigro-striatal pathways (Myers and Undem, 1993, J. Phisiol., 470,665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429; Mccarsonand Krause, 1994, J. Neurosci., 14 (2), 712-720; Arenas et al. 1991, J.Neurosci., 11, 2332-8).

[0004] However, the peptide-like nature of the known antagonists makesthem likely to be too labile from a metabolic point of view to serve aspractical therapeutic agents.

[0005] International Patent Application Number PCT/EP95/02000 describescertain quinoline derivatives and describes inter alia the preparationof the quinolines and their use in medicine. The disclosures ofPCT/EP95/02000 are relevant to the present application only by virtue ofArticle 54(3) of the European Patent Convention.

[0006] We have now discovered certain novel salts of the quinolinederivatives of the compounds of PCT/EP95/02000. The new salts areselective, non-peptide NK₃ antagonists which are far more stable from ametabolic point of view than the known peptidic NK₃ receptor antagonistsand are of potential therapeutic utility in treating pulmonary disorders(asthma, chronic obstructive pulmonary diseases -COPD-, airwayhyperreactivity, cough), skin disorders and itch (for example, atopicdermatitis and cutaneous wheal and flare), neurogenic inflammation andCNS disorders (Parkinson's disease, movement disorders, anxiety,psychosis). These disorders are referred to hereinafter as the PrimaryDisorders.

[0007] The novel NK₃ antagonists of the present invention are also ofpotential therapeutic utility in treating convulsive disorders (forexample epilepsy), renal disorders, urinary incontinence, ocularinflammation, inflammatory pain, eating disorders (food intakeinhibition), allergic rhinitis, neurodegenerative disorders (for exampleAlzheimer's disease), psoriasis, Huntington's disease, and depression(hereinafter referred to as the Secondary Disorders).

[0008] The compounds of the present invention are also useful in theprevention and treatment of disorders of the central nervous system,such as schizophrenia; neurodegenerative disorders, such as AIDS relateddementia, senile dementia of the Alzheimer type and Down's syndrome;demyelinating diseases such as multiple sclerosis and otherneuropathological disorders such as diabetic or peripheral neuropathy,AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia;respiratory diseases such as, bronchopneumonia and bronchospasm;inflammatory diseases such as inflammatory bowel disease, fibrositis,osteoarthritis, rheumatoid arthritis; allergies such as eczema andrhinitis; hypersensivity disorders such as poison ivy; ophthalmicdiseases such as conjunctivitis, vernal conjuctivitis and the like;cutaneous diseases such as contact dermatitis, urticaria and othereczematoid dermatitis; addiction disorders such as alcoholism; stressrelated somatic disorders; reflex sympathetic dystrophy such asshoulder/hand syndrome; dysthymic disorders; adverse immunologicalreactions such as rejection of transplanted tissues and disordersrelated to immune enhancment or suppression such as systhemic lupuserythematosis; gastrointestinal (GI) disorders and diseases of the GItract such as disorders associated with the neuronal control of viscerasuch as ulcerative colitis, Crohn's disease; disorders of the bladderfunction; fibrosing and collagen diseases such as scleroderma andeosinophilic fascioliasis; disorders of the blood flow caused byvasodilation and vasospastic diseases such as angina, migraine andReynaud's disease; pain or nociception, for example, that isattributable to or associated with any of the foregoing conditionsespecially the transmission of pain in migraine (hereinafter referred toas the ‘Further Disorders’).

[0009] According to the present invention there is provided a saltedform of a compound of formula (I) (hereinafter also referred to as ‘aSalt of the invention’):

[0010] or a solvate thereof, wherein Ar is an optionally substitutedphenyl, naphthyl or C₅₋₇ cycloalkdienyl group, or an optionallysubstituted single or fused ring heterocyclic group, having aromaticcharacter, containing from 5 to 12 ring atoms and comprising up to fourhetero-atoms in the or each ring selected from S, O, N;

[0011] R is linear or branched C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkylalkyl, optionally substituted phenyl or phenyl C₁₋₆ alkyl, anoptionally substituted five-membered heteroaromatic ring comprising upto four heteroatom selected from O and N, hydroxy C₁₋₆ alkyl, amino C₁₋₆alkyl, C₁₋₆ alkylaminoalkyl, di C₁₋₆ alkylaminoalkyl, C₁₋₆acylaminoalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆ alkylcarbonyl, carboxy, C₁₋₆alkoxyxcarbonyl, C₁₋₆ alkoxycarbonyl C₁₋₆ alkyl, aminocarbonyl, C₁₋₆alkylaminocarbonyl, di C₁₋₆ alkylaminocarbonyl, halogeno C₁₋₆ alkyl; oris a group —(CH₂)p— when cyclized onto Ar, where p is 2 or 3;

[0012] R₁ and R₂, which may be the same or different, are independentlyhydrogen or C₁₋₆ linear or branched alkyl, or together form a —(CH2)n—group in which n represents 3, 4, or 5; or R₁ together with R forms agroup —(CH₂)q—, in which q is 2, 3, 4 or 5.

[0013] R₃ and R₄, which may be the same or different, are independentlyhydrogen, C₁₋₆ linear or branched alkyl, C₁₋₆ alkenyl, aryl, C₁₋₆alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido,sulphonamido, C₁₋₆ alkoxycarbonyl, trifluoromethyl, acyloxy,phthalimido, amino, mono- and di-C₁₋₆ alkylamino,

[0014] —O(CH₂)_(r)—NT₂, in which r is 2, 3, or 4 and T is hydrogen orC₁₋₆ alkyl or it forms with the adjacent nitrogen a group

[0015] in which V and V₁ are independently hydrogen or oxygen and u is0, 1 or 2;

[0016] —O(CH₂)s—OW in which s is 2, 3, or 4 and W is hydrogen or C₁₋₆alkyl: hydroxyalkyl, aminoalkyl, mono-or di-alkylaminoalkyl, acylamino,alkylsulphonylamino, aminoacylamino, mono- or di-alkylaminoacylamino;with up to four R₃ substituents being present in the quinoline nucleus;or R₄ is a group —(CH2)t— when cyclized onto R₅ as aryl, in which t is1, 2, or 3;

[0017] R₅ is branched or linear C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkylalkyl, optionally substituted aryl, or an optionallysubstituted single or fused ring heterocyclic group, having aromaticcharacter, containing from 5 to 12 ring atoms and comprising up to fourhetero-atoms in the or each ring selected from S, O, N;

[0018] X is O, S, or N—C≡N; characterised in that the salt comprises acompound of formula (I) in anionic form and a salting cation.

[0019] Suitably, the salt is a compound of formula (A):

S^(t−)M^(t+)  (A)

[0020] or a solvate thereof, wherein,

[0021] t is an integer 1, 2 or 3;

[0022] M^(t+) is a salting cation; and

[0023] S^(t−) is an anion provided by an appropriate compound of theabove defined formula (I).

[0024] Suitable saltine cations M^(t+) include metal ions and organiccations, in particular pharmaceutically acceptable metal ions andorganic cations.

[0025] Suitable pharmaceutically acceptable metal ions include thoseions provided by aluminium, alkali metals such as lithium, sodium orpotassium, alkaline earth metals such as calcium or magnesium.

[0026] Suitable pharmaceutically acceptable organic cations includeammonium or substituted ammonium ions, for example those from loweralkylamines such as triethylamine, hydroxy alkylamines such as2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine ortri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine,or with procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine,dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine,N-methylglucamine or bases of the pyridine type such as pyridine,collidine, quinine or quinoline.

[0027] A particular salting, cation M^(t+) is an alkali metal ion, forexample a sodium ion.

[0028] An appropriate compound of formula (A) is a compound which iscapable of forming an anion S^(t−) and favourably includes compounds offormula (A) which comprise acidic moieties, for example those whichcomprise a carboxy group and/or a phenolic hydroxy group.

[0029] Suitably, t is 1 or 2, for example 1.

[0030] Particular values for the variables of formula (I) are set outbelow. It will be appreciated that any appropriate compound of formula(I) comprising these variables will be characterised in that it iscapable of forming a anion S^(t−). Thus:

[0031] Examples of Ar are phenyl, optionally substituted by hydroxy,halogen, C₁₋₆ alkoxy or C₁₋₆ alkyl. Examples of halogen are chlorine andfluorine, an example of C₁₋₆ alkoxy is methoxy and an example of C₁₋₆alkyl is methyl.

[0032] Examples of Ar as a heterocyclic group are thienyl and pyridyl.

[0033] Examples of Ar as a C₅₋₇ cycloalkdienyl group is cyclohexadienyl.

[0034] Examples of R are as follows:

[0035] C₁₋₈ alkyl: methyl, ethyl, n-propyl, iso-propyl, n-butyl, heptyl;

[0036] phenyl C₁₋₆ alkyl: benzyl;

[0037] hydroxy C₁₋₆ alkyl: —CH₂OH, —CH₂CH₂OH, CH(Me)OH;

[0038] amino C₁₋₆ alkyl: —CH₂NH₂;

[0039] di C₁₋₆ alkylaminoalkyl: —CH₂NMe₂;

[0040] C₁₋₆ alkoxylalkyl: CH₂OMe;

[0041] C₁₋₆ alkylcarbonyl: COMe;

[0042] C₁₋₆ alkoxycarbonyl: COOMe;

[0043] C₁₋₆ alkoxycarbonyl C₁₋₆ alkyl: CH₂COOMe;

[0044] C₁₋₆ alkylaminocarbonyl: CONHMe;

[0045] di C₁₋₆ alkylaminocarbonyl: CONMe₂, CO(1-pyrrolidinyl);

[0046] halogen C₁₋₆ alkyl: trifluoromethyl;

[0047] —(CH₂)p— when cyclized onto Ar:

[0048] Example of R₁ and R₂ as C₁₋₆ alkyl is methyl;

[0049] example of R₁ together with R forming a group—(CH₂)q— isspirocyclopentane.

[0050] Examples of R₃ and R₄ are methyl, ethyl, n-propyl, n-butyl,methoxy, hydroxy, amino, chlorine, fluorine, bromine, acetyloxy,2-(dimetylamino)ethoxy, 2-(phthalimido)ethoxy, aminoethoxy,2-(1-pyrrolidinyl)ethoxy, phthalimido, dimethylaminopropoxy,dimethylaminoacetylamino, acetylamino, dimethylaminomethyl and phenyl.

[0051] Examples of R₅ are cyclohexyl, phenyl optionally substituted asdefined for Ar above; examples of R₅ as a heterocyclic group are furyl,thienyl, pyrryl, thiazolyl, benzofuryl and pyridyl.

[0052] A preferred group of compounds of formula (D) are those in which:

[0053] Ar is phenyl, optionally substituted by C₁₋₆ alkyl or halogen;thienyl or a

[0054] C₅₋₇ cycloalkdienyl group;

[0055] R is C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, hydroxyC₁₋₆ alkyl;

[0056] R₁ and R₂ are each hydrogen or C₁₋₆ alkyl;

[0057] R₃ is hydrogen, hydroxy, halogen, C₁₋₆ alkoxy, C₁₋₆ alkyl;

[0058] R₄ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, amino, halogen,aminoalkoxy, mono- or di-alkylaminoalkoxy, mono- or di-alkylaminoalkyl,phthalimidoalkoxy, mono- or di-alkylaminoacylamino and acylamino;

[0059] R₅ is phenyl, thienyl, furyl, pyrryl and thiazolyl.

[0060] A further preferred group of compounds of formula (I) are thosein which:

[0061] Ar is phenyl, 2-chlorophenyl, 2-thienyl or cyclohexadienyl;

[0062] R is methyl, ethyl, n-propyl, —COOMe, —COMe;

[0063] R₁ and R₂ are each hydrogen or methyl;

[0064] R₃ is hydrogen, methoxy, or hydroxy;

[0065] R₄ is hydrogen, methyl, ethyl, methoxy, hydroxy, amino, chlorine,bromine, dimethylaminoethoxy, 2-(phthalimido)ethoxy, aminoethoxy,2-(1-pyrrolidinyl)ethoxy, dimethylaminopropoxy,dimethylaminoacetylamino, acetylamino, and dimethylaminomethyl.

[0066] R₅ is phenyl, 2-thienyl, 2-furyl, 2-pyrryl, 2-thiazolyl and3-thienyl;

[0067] and X is oxygen.

[0068] A preferred sub-group of compounds within the scope of formula(I) above is of formula (Ia):

[0069] in which:

[0070] R, R₂, R₃ and R₄ are as defined in formula (I), and Y and Z,which may be the same or different, are each Ar as defined in formula(I).

[0071] A particularly preferred group of compounds of formula (Ia) arethose of formula (Ib) in which the group R is oriented downward and Hupward.

[0072] The compounds of formula (I) or their solvates are preferably inpharmaceutically acceptable or substantially pure form. Bypharmaceutically acceptable form is meant, inter alia, of apharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels.

[0073] One particular compound is(S)-(−)-N-(α-ethylbenzyl)-3-hydroxy-2-phenyl-4-quinoline carboxamide.

[0074] A substantially pure form will generally contain at least 50%(excluding normal pharmaceutical additives), preferably 75%, morepreferably 90% and still more preferably 95% of the Salt of theinvention or a solvate thereof.

[0075] One preferred pharmaceutically acceptable form is the crystallineform, including such form in pharmaceutical composition. In the case ofsalts and solvates the additional ionic and solvent moieties must alsobe non-toxic.

[0076] Suitable solvates are pharmaceutically acceptable solvates.

[0077] Examples of pharmaceutically acceptable solvates of a Salt of theinvention include hydrates, such as sesquihydrates.

[0078] The compounds of formula (I) may have at least one asymmetriccentre and therefore may exist in more than one stereoisomeric form. Thecompounds of formula (A) include all such forms and mixtures thereof,including racemates.

[0079] The invention also provides a process for the preparation of aSalt of the invention, or a solvate thereof, which process comprisesadmixing a source of S^(t−) anions and a source of salting cationsM^(t+); and thereafter, as required, preparing a solvate of the Salt ofthe invention so formed.

[0080] Suitable conditions for preparing the salt of formula (A) includeconventional salification methods, the particular conditions used beingdependent upon the particular nature of the salting ions chosen, inparticular the source of S^(t−).

[0081] Generally, the source of S^(t−) ions and source of salting cationM^(t+) are admixed in an alkanol, suitably an alkanol containing water,at any temperature providing a suitable rate of formation of therequired product, usually at ambient temperature or a slightly elevatedtemperature, such as a temperature in the range of from 25 to 50° C.,for example 40° C.

[0082] When the salting cation M^(t+) is a metal ion, a suitable sourceof M^(t+) is a metal hydroxide, for example sodium hydroxide forcompounds where M^(t+) is sodium.

[0083] Suitable alkanols are C₁₋₃ alkanols, for example methanol.

[0084] When the solvent is an alkanol it may contain up to 25% byvolume, more usually up to 10% by volume, of water.

[0085] Conveniently, a solution of the source of salting cation M^(t+)ions in water is admixed with a solution of the appropriate compound offormula (I) in an alkanol.

[0086] The resulting product may be obtained by conventionalcrystallisation/recrystallisation methods.

[0087] Conveniently, the produce is crystallised from the reactionsolvent Recrystallisation is conveniently effected using an alternativesolvent such as toluene or isopropanol or mixtures thereof.

[0088] A suitable source of S^(t−) ions is a compound of formula (I)which comprises a carboxy group and/or a phenolic hydroxy group.

[0089] A compound of formula (I) may be prepared by reacting a compoundof formula (III):

[0090] in which R′, R′₁, R′₂ and Ar′are R, R₁, R₂ and Ar as defined forformula (I) or a group or atom convertible to R, R₁, R₂ and Ar, with acompound of formula (II)

[0091] or an active derivative thereof, in which R′₃, R′₄, R′₅ and X′are R₃, R₄, R₅ and X as defined for formula (I) or a group convertibleto R₃, R₄, R₅ and X, to form a compound of formula (Ic)

[0092] and optionally thereafter performing one or more of the followingsteps:

[0093] (a) where R′, R′₁ to R′₅, Ar′ and X′ are other than R, R₁ to R₅,Ar and X, converting any one of R′, R′₁ to R′₅, Ar′ and X′ to R, R₁ toR₅, Ar and X to obtain a compound of formula (I),

[0094] (b) where R′, R′₁ to R′₅, Ar′ and X′ are R, R₁ to R₅, Ar and X,converting any one of R, R₁ to R₅, Ar and X to another R, R₁ to R₅, Arand X, to obtain a compound of formula (I),

[0095] (c) forming a salt and/or solvate of the obtained compound offormula (Ic).

[0096] Suitable active derivatives of the compounds of formula (II) areacid halides (preferably chlorides), acid azides or acid anhydrides.Another suitable derivative is a mixed anhydride formed between the acidand an alkyl chloroformate; another suitable derivative is an activatedester such as a cyanomethyl ester, thiophenyl ester, p-nitrophenylester, p-nitrothiophenyl ester, 2,4,6-trichlorophenyl ester,pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phtalimidoester, N-hydroxypiperidine ester, N-hydroxysuccinimide ester, N-hydroxybenzotriazole ester; or the carboxy group may be activated using acarbodiimide or N,N′-carbonyldiimidazole.

[0097] For example, in standard methods well known to those skilled inthe art, the compounds of formula (III) may be coupled:

[0098] (a) with an acid chloride in the presence of an inorganic ororganic base in a suitable aprotic solvent such as dimethylformamide(DMF) at a temperature in a range from −70 to 50° C. (preferably in arange from −10 to 20° C.),

[0099] (b) with the acid in the presence of a suitable condensing agent,such as for example N,N′-carbonyl diimidazole (CDI) or a carbodiimidesuch as dicyclohexylcarbodiimide (DCC) orN-dimethylaminopropyl-N′-ethylcarbodiimide and N-hydroxybenzotriazole(HOBT) to maximise yields and avoid racemization processes (Synthesis,453, 1972) in an aprotic solvent such as a mixture of acetonitrile(MeCN) and tetrahydrofuran (THF) in a ratio from 1:9 to 7:3,respectively, at a temperature in a range from −70 to 50° C. (preferablyin a range from −10 to 25° C) (see Scheme 1),

[0100] (c) with a mixed anhydride generated in situ from the acid and analkyl (for example isopropyl) chloroformate in a suitable aproticsolvent such as dichloromethane at a temperature in a range from −70 to50° C. (preferably in a rance from −20 to 20° C.).

[0101] It will be appreciated that a compound of formula (Ic) may beconverted to a compound of formula (I), or one compound of formula (I)may be converted to another compound of formula (I), by interconversionof suitable substituents. Thus, certain compounds of formula (D) and(Ic) are useful intermediates in forming other compounds of the presentinvention.

[0102] For example R′₂ may be hydrogen and converted to R₂ alkyl group,for example methyl, by conventional amide alkylation procedures(Zabicky, The chemistry of amides; Interscience, London, 1970, p. 749).When X′ is oxygen, it may be converted to X sulphur by standardthioamide formation reagents, such as P₂S₅ (Chem. Rev., 61, 45, 1961 orAngew. Chem., 78, 517, 1966) or the Lawesson reagent (Tetrahedron, 41,5061, 1985). When Ar′ or R′₅ is a methoxy substituted phenyl, it may beconverted to another Ar′ or R′₅ hydroxy substituted phenyl by standarddemethylation procedures via Lewis acids, such as boron tribromide(Synthesis, 249, 1983) or mineral acids, such as hydrobromic orhydroiodic acid. When R is an alkoxycarbonyl group, for examplemethoxycarbonyl, it may be converted to another R, such asethoxycarbonyl by transesterification with an appropriate alcohol at atemperature in a range from 20 to 120° C., carboxy by hydrolysis inacidic or basic medium, aminocarbonyl, alkylaminocarbonyl ordialkylaminocarbonyl by transamidation with ammonia, a primary amine ora secondary amine in methanol as solvent at a temperature in a ranaefrom 10 to 120° C., optionally in the presence of a catalytic amount ofNaCN (J. Org. Chem., 52, 2033, 1987) or by using trimethylaluminium(Me₃Al) (Tetrahedron Letters, 48, 4171, 1977), hydroxymethyl by aselective metal hydride reduction, such as lithium borohydride reduction(Tetrahedron, 35, 567, 1979) or sodium borohydride reduction in THF+MeOH(Bull. Chem. Soc. Japan, 57, 1948, 1984 or Synth. Commun., 12, 463,1982), alkylcarbonyl by acyl chloride formation and subsequent reactionwith alkylmagnesium halides in THF as solvent at a temperature in arange from −78 to 30° C. (Tetrahedron Letters, 4303, 1979) or withalkylcadmium halides or dialkylcadmium in the presence of MgCl₂ or LiCl(J. Org. Chem., 47, 2590, 1982). Another group which R′ asmethoxycarbonyl can be converted into is a substituted heteroaromaticring, such as an oxadiazole (J. Med. Chem., 34, 2726, 1991).

[0103] Scheme 2 summarizes some of the above described procedures toconvert a compound of formula (Ic) or (I) in which X′ is oxygen, R′ isCOOMe, Ar′ and R′₁ to R′₅ are as described for formula (I) to anothercompound of formula (I).

[0104] Solvates of the compounds of formula (I) may be formed bycrystallization or recrystallization from the appropriate solvent. Forexample, hydrates may be formed by crystallization or recrystallizationfrom aqueous solutions, or solutions in organic solvents containingwater.

[0105] As mentioned before, the compounds of formula (I) may exist inmore than one stereoisomeric form and the processes described herein mayproduce racemates as well as enantiomerically pure forms. To obtain pureenantiomers, appropriate enantiomerically pure primary or secondaryamines of formula (IIId) or (IIIe)

[0106] are reacted with compounds of formula (II), to obtain compoundsof formula (I′d) or (I′e).

[0107] Compounds of formula (I′d) or (I′e) may subsequently be convertedto compounds of formula (Id) or (le) by the methods of conversionmentioned before.

[0108] Compounds of formula (II) are known compounds or can be preparedfrom known compounds by known methods.

[0109] For example, the compound of formula (II), in which X′ is oxygen,R′₃, R′₄ and R′₅ are hydrogen is described in Pfitzinger, J. Prakt.Chem., 38, 582, 1882 and in Pfitzinger, J. Prakt. Chem., 56, 293, 1897;the compound of formula (II), in which X′ is oxygen, R′₃ and R′₄ arehydrogen and R′₅ is 2-pyridyl is described in Risaliti, Ric. Scient.,28, 561, 1958; the compound of formula (II), in which X′ is oxygen, R′₃and R′₄ are hydrogen and R′₅ is o-, m- and p-chlorophenyl,o-fluorophenyl and 3,4-dichlorophenyl are described in Brown et al., J.Am. Chem. Soc., 68, 705, 1946; the compound of formula (II), in which X′is oxygen, R′₃ and R′₄ are hydrogen and R′₅ is p-methoxyphenyl isdescribed in Ciusa and Luzzatto, Gazz. Chim. Ital., 44, 64, 1914; thecompound of formula (II), in which X′ is oxygen, R′₃ and R′₄ arehydrogen and R′₅ is m-trifluoromethylphenyl is described in Shargier andLalezari, J. Chem. Eng. Data, 8, 276, 1963; the compound of formula(II), in which X′ is oxygen, R′₃ and R′₄ are hydrogen and R′₅ isp-fluorophenyl is described in Bu Hoi et al., Rec Trav. Chim., 68, 781,1949; the compound of formula (II), in which X′ is oxygen, R′₃ and R′₄are hydrogen and R′₅ is p-methylphenyl is described in Prevost et al.,Compt. Rend. Acad. Sci., 258, 954, 1964; the compound of formula (II),in which X′ is oxygen, R′₃ and R′₄ are hydrogen and R′₅ is p-bromophenylis described in Nicolai et al., Eur. J. Med. Chem., 27, 977, 1992; thecompound of formula (II), in which X′ is oxygen, R′₄ and R′₅ arehydrogen and R′₃ is 6-methyl is described in Buchmann and Howton, J. Am.Chem. Soc., 68, 2718, 1946; the compound of formula (II), in which X′ isoxygen, R′₄ and R′₅ are hydrogen and R′₃ is 8-nitro is described inBuchmann et al, J. Am Chem. Soc., 69, 380, 1947; the compound of formula(II), in which X′ is oxygen, R′₄ is hydrogen, R′₃ is 6-chloro, R′₅ isp-chlorophenyl is described in Lutz et al., J. Am. Chem. Soc., 68, 1813,1946; the compound of formula (II), in which X′ is oxygen, R′₃ and R′₄are hydrogen and R′₅ is 2-thiazolyl is described in Eur. Pat. Appl. EP112,776; compounds of formula (II), in which X′ is oxygen, R′₃ is8-trifluoromethyl, R′₄ is hydrogen and R′₅ are phenyl, o- andp-fluorophenyl, 3,4-dichlorophenyl, p-methoxyphenyl are described inNicolai et al., Eur. J. Med. Chem., 27, 977, 1992; compounds of formula(II), in which X′ is oxygen, R′₃ is 6-bromo, R′₄ is hydrogen and R′₅ arephenyl or p-fluorophenyl are described in Nicolai et al., Eur. J. Med.Chem., 27, 977, 1992; other compounds of formula (II) are described inGer. Offen. DE 3,721,222 and in Eur. Pat. Appl. EP 384,313.

[0110] Compounds of formula (III), (IIId) and (IIIe) are commerciallyavailable compounds or can be prepared from known compounds by knownmethods (for example, compounds of formula (III) in which R′ isalkoxycarbonyl, R′₁ and R′₂ are hydrogen and Ar′ is as defined for thecompounds of formula (I), are described in Liebigs Ann. der Chemie, 523,199, 1936).

[0111] The activity of the compounds of formula (A) as NK₃ receptorantagonists in standard tests indicates that they are of potentialtherapeutic utility in the treatment of Disorders herein before referredto.

[0112] Accordingly, the present invention also provides a Salt of theinvention, or a pharmaceutically acceptablesolvate thereof, for use asan active therapeutic substance.

[0113] The present invention further provides a pharmaceuticalcomposition comprising a Salt of the invention, or a pharmaceuticallyacceptable solvate thereof, and a pharmaceutically acceptable carrier.

[0114] The present invention also provides the use of a Salt of theinvention, or a pharmaceutically acceptable solvate thereof, in themanufacture of a medicament for the treatment of the Primary. Secondaryor Further Disorders disclosed herein before.

[0115] Such a medicament and a composition of this invention, may beprepared by admixture of a compound of the invention with an appropriatecarrier. It may contain a diluent, binder, filler, disintegrant,flavouring agent, colouring agent, lubricant or preservative inconventional manner.

[0116] These conventional excipients may be employed for example as inthe preparation of compositions of known agents for treating theconditions.

[0117] Preferably, a pharmaceutical composition of the invention is inunit dosage form and in a form adapted for use in the medical orveterinarial fields. For example, such preparations may be in a packform accompanied by written or printed instructions for use as an agentin the treatment of the conditions.

[0118] The suitable dosage range for the compounds of the inventiondepends on the compound to be employed and on the condition of thepatient It will also depend, inter alia, upon the relation of potency toabsorbability and the frequency and route of administration.

[0119] The compound or composition of the invention may be formulatedfor administration by any route, and is preferably in unit dosage formor in a form that a human patient may administer to himself in a singledosage. Advantageously, the composition is suitable for oral, rectal,topical, parenteral, intravenous or intramuscular administration.Preparations may be designed to give slow release of the activeingredient.

[0120] Compositions may, for example, be in the form of tablets,capsules, sachets, vials, powders, granules, lozenges, reconstitutablepowders, or liquid preparations, for example solutions or suspensions,or suppositories.

[0121] The compositions, for example those suitable for oraladministration, may contain conventional excipients such as bindingagents, for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinyl-pyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable setting agents such as sodiumlauryl sulphate.

[0122] Solid compositions may be obtained by conventional methods ofblending, filling. tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. When the composition is in theform of a tablet, powder, or lozenge, any carrier suitable forformulating solid pharmaceutical compositions may be used, examplesbeing magnesium stearate, starch, glucose, lactose, sucrose, rice flourand chalk. Tablets may be coated according to methods well known innormal pharmaceutical practice, in particular with an enteric coating.The composition may also be in the form of an ingestible capsule, forexample of gelatin containing the compound, if desired with a carrier orother excipients.

[0123] Compositions for oral administration as liquids may be in theform of, for example, emulsions, syrups, or elixirs, or may be presentedas a dry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may contain conventional additivessuch as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose,aluminium stearate gel, hydrogenated edible fats; emulsifying agents,for example lecithin, sorbitan monooleate, or acacia; aqueous ornon-aqueous vehicles, which include edible oils, for example almond oil,fractionated coconut oil, oily esters, for example esters of glycerine,or propylene glycol, or ethyl alcohol, glycerine, water or normalsaline; preservatives, for example methyl or propyl p-hydroxybenzoate orsorbic acid; and if desired conventional flavouring or colouring agents.

[0124] The compounds of this invention may also be administered by anon-oral route. In accordance with routine pharmaceutical procedure, thecompositions may be formulated, for example for rectal administration asa suppository. They may also be formulated for presentation in aninjectable form in an aqueous or non-aqueous solution, suspension oremulsion in a pharmaceutically acceptable liquid, e.g. sterilepyrogen-free water or a parenterally acceptable oil or a mixture ofliquids. The liquid may contain bacteriostatic agents, anti-oxidants orother preservatives, buffers or solutes to render the solution isotonicwith the blood, thickening agents, suspending agents or otherpharmaceutically acceptable additives. Such forms will be presented inunit dose form such as ampoules or disposable injection devices or inmulti-dose forms such as a bottle from which the appropriate dose may bewithdrawn or a solid form or concentrate which can be used to prepare aninjectable formulation.

[0125] The compounds of this invention may also be administered byinhalation, via the nasal or oral routes. Such administration can becarried out with a spray formulation comprising a compound of theinvention and a suitable carrier, optionally suspended in, for example,a hydrocarbon propellant.

[0126] Preferred spray formulations comprise micronised compoundparticles in combination with a surfactant, solvent or a dispersingagent to prevent the sedimentation of suspended particles. Preferably,the compound particle size is from about 2 to 10 microns.

[0127] A further mode of administration of the compounds of theinvention comprises transdermal delivery utilising a skin-patchformulation. A preferred formulation comprises a compound of theinvention dispersed in a pressure sensitive adhesive which adheres tothe skin, thereby permitting the compound to diffuse from the adhesivethrough the skin for delivery to the patient. For a constant rate ofpercutaneous absorption, pressure sensitive adhesives known in the artsuch as natural rubber or silicone can be used.

[0128] As mentioned above, the effective dose of compound depends on theparticular compound employed, the condition of the patient and on thefrequency and route of administration. A unit dose will generallycontain from 20 to 1000 mg and preferably will contain from 30 to 500mg. in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500mgt. The composition may be administered once or more times a day forexample 2, 3 or 4 times daily, and the total daily dose for a 70 kaadult will normally be in the range 100 to 3000 mg. Alternatively theunit dose will contain from 2 to 20 mg of active ingredient and beadministered in multiples, if desired, to give the preceding daily dose.

[0129] No unacceptable toxicological effects are expected with compoundsof the invention when administered in accordance with the invention.

[0130] The present invention also provides a method for the treatmentand/or prophylaxis of the Primary, Secondary or Further Disorders inmammals, particularly humans, which comprises administering to themammal in need of such treatment and/or prophylaxis an effective,non-toxic pharmceutically acceptable amount of a Salt of the inventionor a pharmaceutically acceptable solvate thereof.

[0131] The activity of the compounds of the present invention, as NK₃ligands, is determined by their ability to inhibit the binding of theradiolabelled NK₃ ligands, [¹²⁵I]-[Me-Phe⁷]-NKB or [³H]-Senktide, toguinea-pig and human NK₃ receptors (Renzetti et al., 1991, Neuropeptide,18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et a, 1994,Biochem. Biophys. Res. Commun., 198(3), 967-972).

[0132] The bindings assays utilized allow the determination of theconcentration of the individual compound required to reduce by 50% the[¹²⁵I]-[Me-Phe⁷]-NKB and [³H]-Senktide specific binding to NK₃ receptorin equilibrium conditions (IC50).

[0133] Binding assays provide for each compound tested a mean IC₅₀ valueof 2-5 separate experiments performed in duplicate or triplicate. Themost potent compounds of the present invention show IC₅₀ values in therange 1-1000 nM; in particular, in guinea-pig cortex membranes bydisplacement of [³H]-Senktide, the compound of the Example 1 displays aK_(i) of 4.8 nM (n=3). The NK₃-antagonist activity of the compounds ofthe present invention is determined by their ability to inhibitsenktide-induced contraction of the guinea-pig ileum (Maggi et al, 1990,Br. J. Pharmacol., 101, 996-1000) and rabbit isolated iris sphinctermuscle (Hall et al., 1991, Eur. J. Pharmacol., 199, 9-14) and human NK₃receptors-mediated Ca⁺⁺ mobilization (Mochizuki et al, 1994, J. Biol.Chem., 269, 9651-9658). Guinea-pig and rabbit in-vitro functional assaysprovide for each compound tested a mean K_(B) value of 3-8 separateexperiments, where K_(B) is the concentration of the individual compoundrequired to produce a 2-fold rightward shift in theconcentration-response curve of senktide. Human receptor functionalassay allows the determination of the concentration of the individualcompound required to reduce by 50% (IC₅₀ values) the Ca⁺⁺ mobilizationinduced by the agonist NKB. In this assay, the compounds of the presentinvention behave as antagonists.

[0134] The therapeutic potential of the compounds of the presentinvention in treating the conditions can be assessed using rodentdisease models.

[0135] The following Description illustrates the preparation of anintermediate, whereas the Example illustrates the preparation of acompound of the present invention but they do not limit the invention inany way.

Experimental Details

[0136] DESCRIPTION 1:

[0137] (S)-(−)-N-(α-ethylbenzyl)-3-hydroxy-2phenyl-4-quinolinecarboxamide

[0138] 2.49 g (9.4 mmols) of 3-hydroxy-2-phenyl-4-quinoline carboxylicacid (CAS [485-89-2]) were suspended in 150 ml of a mixture of THF/MeCN7:3, respectively; 1.40 g (10.3 mmols) of 1-hydroxybenzotriazole (HOBT)were added to the suspension and then 1.27 g (9.4 mmols) of(S)-(−)-1-phenylpropylamine, dissolved in 20 ml of methylene chloridewere added dropwise over 10 minutes period. The reaction mixture wasstirred at room temperature for 30 minutes and then 2.13 g (10.3 mmols)of dicyclohexylcarbodiimide (DCC), dissolved in 20 ml of methylenechloride, were added dropwise and the reaction stirred overnight. 20 mlof H₂O were added and the reaction stirred 30 minutes, then the solventwas evaporated in vacuo to dryness. The residue was taken up in EtOAc,the precipitated dicyclohexylurea (DCU) was filtered off and thefiltrate washed with water, 20% citric acid, 5% NaHCO₃, brine and theorganic layer dried over Na₂SO₄ and the solvent evaporated in vacuo. Theresidue was purified by silica-gel (60-240 mesh) flash columnchromatography, eluting with a mixture of hexane/EtOAc 9:1, containingincreasing amounts of EtOAc, until the ratio 7:3. The purified productwas crystallized from i-PrOH to yield 1.75 g of the title compound as awhite solid.

[0139] C₂₅H₂₂N₂O₂

[0140] M.P.=168-168.4° C.

[0141] M.W.=382.47

[0142] [α]_(D) ²⁰=−28.5 (c=0.5, MeOH)

[0143] Elemental analysis: Calcd. C, 78.51; H, 5.80; N, 7.33; Found C.78.49; H, 5.84; N, 7.86.

[0144] I.R. (Kbr): 3370; 1625; 1525 cm−1.

[0145] 300 MHz ¹H-NMR (DMSO-₆): δ: 9.80(s, 1H); 9.11 (d, 1H); 8.00-7.94(m, 3H); 7.61-7.42 (m, 8H); 7.38 (dd, 2H); 7.28 (dd, 1H); 5.06 (dt, 1H);1.82 (ddq, 2H); 0.97 (t, 3H).

[0146] MS (EI; TSQ 700; source 200° C.; 70 eV; 200 μA): 382 (M+.); 264;247; 219.

EXAMPLE 1 (S)-(+)-N-(α-ethylbenzyl)-3-hydroxy-2-phenyl-4-quinolineCarboxamide Sodium Salt Sesquihydrate

[0147] 500 mg, (1.31 mmols) of(S)-(−)-N-(α-ethylbenzyl)-3-hydroxy-2-phenyl-4-quinoline carboxamide(the compound of Description 1, dissolved in 20 ml of MeOH containing1.31 ml of 1N NaOH (1.31 mmols), were stirred at 40° C. for 30 minutesand then the solvent was evaporated in vacuo to dryness. Crystallizationof the residue from a mixture of toluene and iPrOH yielded 240 m; of thetitle compound as a yellow solid.

[0148] C₂₅H₂₁N₂O₂Na 1.5 H₂O

[0149] M.P.=110° C. (dec.)

[0150] M.W.=431.48

[0151] [α]_(s) ²⁰ =+169.81 (c=0.5, MeOH)

[0152] Elemental analysis: Calcd. C, 69.59; H, 5.61; N, 6.49; Na, 5.33Found C, 69.07; H, 5.45; N, 6.05; Na, 5.49.

[0153] I.R. (nujol): 1640; 1460; 1380 cm−1.

[0154] 300 MHz ¹H-NMR (DMSO- d₆): δ: 13.3 (d, 1H); 9.4 (d, 1H); 8.23 (d,2H); 7.60 (dd, 1H); 7.41-7.09 (m, 9H); 6.09 (ddd, 1H); 5.08 (dt, 1H);1.80 (m, 2H); 0.91 (t, 3H).

1. A compound of formula (I):

or a solvate thereof, wherein Ar is an optionally substituted phenyl,naphthyl or C₅₋₇ cycloalkdienyl group, or an optionally substitutedsingle or fused ring heterocyclic group, having aromatic character,containing from 5 to 12 ring atoms and comprising up to fourhetero-atoms in the or each ring selected from S, O, N; R is linear orbranched C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkylalkyl, optionallysubstituted phenyl or phenyl C₁₋₆ alkyl, an optionally substitutedfive-membered heteroaromatic ring comprising up to four heteroatomselected from O and N, hydroxy C₁₋₆ alkyl, amino C₁₋₆ alkyl, C₁₋₆alkylaminoalkyl, di C₁₋₆ alkylaminoalkyl, C₁₋₆ acylaminoalkyl, C₁₋₆alkoxyalkyl, C₁₋₆ alkylcarbonyl, carboxy, C₁₋₆ alkoxyxcarbonyl, C₁₋₆alkoxycarbonyl C₁₋₆ alkyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl, diC₁₋₆ alkylaminocarbonyl, halogeno C₁₋₆ alkyl; or is a group —(CH₂)p—when cyclized onto Ar, where p is 2 or 3; R₁ and R₂, which may be thesame or different, are independently hydrogen or C₁₋₆ linear or branchedalkyl, or together form a —(CH2)n— group in which n represents 3, 4, or5; or R₁ together with R forms a group —(CH₂)q—, in which q is 2, 3, 4or 5, R₃ and R₄, which may be the same or different, are independentlyhydrogen, C₁₋₆ linear or branched alkyl, C₁₋₆ alkenyl, aryl, C₁₋₆alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido,sulphonamido, C₁₋₆ alkoxycarbonyl, trifluoromethyl, acyloxy,phthalimido, amino, mono- and di-C₁₋₆ alkylamino, —O(CH₂)_(r)—NT2, inwhich r is 2, 3, or 4 and T is hydrogen or C₁₋₆ alkyl or it forms withthe adjacent nitrogen a group

in which V and V₁ are independently hydrogen or oxygen and u is 0,1 or2; —O(CH₂)s—OW in which s is 2, 3, or 4 and W is hydrogen or C₁₋₆ alkyl;hydroxyalkyl, aminoalkyl, mono-or di-alkylaminoalkyl, acylamino,alkylsulphonylamino, aminoacylamino, mono- or di-alkylaminoacylamino;with up to four R₃ substituents being present in the quinoline nucleus;or R₄ is a group —(CH₂)t— when cyclized onto R₅ as aryl, in which t is1, 2, or 3; R₅ is branched or linear C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkylalkyl, optionally substituted aryl, or an optionallysubstituted single or fused ring heterocyclic group, having aromaticcharacter, containing from 5 to 12 ring atoms and comprising up to fourhetero-atoms in the or each ring selected from S, O, N; X is O, S, orN—C≡N; characterised in that salt comporises a compound of formula (I)in anionic form and a salting cation.
 2. A compound according to claim 1of formula (A): S^(t−)M^(t+)  (A) or a solvate thereof, wherein; t is aninteger 1, 2 or 3; M^(t+) is a salting cation; and S^(t−) is an anionprovided by an appropriate compound of formula (I) in claim
 1. 3. Acompound according to claim 2, wherein saltine cation M^(t+) is a metalions or an organic cation.
 4. A compound according to claim 2, whereinmetal salting cation M^(t+) is selected from aluminium, alkali metal oralkaline earth metal ions.
 5. A compound according to claim 2, whereinorganic salting cation M^(t+) is selected from ammonium or substitutedammonium ions.
 6. A compound according to claim 2, wherein saltinecation M^(t+) is a sodium ion.
 7. A compound according to any one ofclaims 2 to 6, wherein t is 1 or
 2. 8. A compound according to claim 1,being (S)-(+)-N-(α-ethylbenzyl)-3-hydroxy-2-phenyl-4-quinolinecarboxamide sodium salt sesquihydrate.
 9. A process for the preparationof a compound according to claim 1, which process comprises admixing acompound of formula (I) and a source of salting cation; and thereafter,as required, preparing a solvate of the salt so formed.
 10. Apharmaceutical composition comprising a compound according to claim 1,or a pharmaceutically acceptable solvate thereof, and a pharmaceuticallyacceptable carrier.
 11. A compound according to claim 1, or apharmaceutically acceptable solvate thereof, for use as an activetherapeutic substance.
 12. The use of a compound according to claim 1,or a pharmaceutically acceptable solvate thereof, in the manufacture ofa medicament for the treatment off the Primary, Secondary or FurtherDisorders disclosed herein before.
 13. A method for the treatment and/orprophylaxis of the Primary, Secondary or Further Disorders in mammalswhich comprises administering to the mammal in need of such treatmentand/or prophylaxis an effective, non-toxic pharmaceutically acceptableamount of a compound according to claim 1 or a pharmaceuticallyacceptable solvate thereof.